Nucleoside derivatives often are potent anti-viral (e.g., HIV, HCV, Herpes simplex, CMV) and anti-cancer chemotherapeutic agents. Unfortunately their utility is often limited by two factors. Firstly, poor pharmacokinetic properties frequently limit the absorption of the nucleoside from the gut and the intracellular concentration of the nucleoside derivatives and, secondly, suboptimal physical properties restrict formulation options which could be employed to enhance delivery of the active ingredient.
Prodrugs (P. Ettmayer et al., J. Med. Chem. 2004 47(10):2393-2404; K. Beaumont et al., Curr. Drug Metab. 2003 4:461-485; H. Bundgaard, Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities in Design of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amersterdam 1985; G. M. Pauletti et al. Adv. Drug Deliv. Rev. 1997 27:235-256; R. J. Jones and N. Bischofberger, Antiviral Res. 1995 27; 1-15 and C. R. Wagner et al., Med. Res. Rev. 2000 20:417-45) afford one technique to improve absorption of the drug. Typical examples of prodrugs include compounds that have biologically labile protecting groups linked to a functional moiety of the active compound. Alkylation, acylation or other lipophilic modification of the hydroxy group(s) on the sugar moiety have been utilized in the design of pronucleotides. These pronucleotides can be hydrolyzed or dealkylated in vivo to generate the active compound. Unfortunately many otherwise useful prodrugs exhibit limited aqueous solubility which present a significant formulation challenge.
4-Amino-1-(5-azido-3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (II) was found to be an useful inhibitor of HCV NS5B polymerase; however, the nucleoside exhibited insufficient bioavailabilty. (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-bis-iso-butyryloxy-tetrahydro-furan-2-ylmethyl isobutyrate hydrochloride salt (I) was found to be efficiently absorbed and revert to I in plasma. Unfortunately 1 forms a gel when exposed to water which limits its solubility. The term gel herein refers to a biphasic dispersion containing water and small solid hydrated particles of I. The solid particles dispersed in water are difficult to handle and process into the final dosage form. The gel hinders dissolution of the active ingredient after administration. Thus effective use of I in HCV therapy requires formulation which avoids forming a gel during processing, has suitable pharmaceutical characteristics and dissolves effectively in the gut and produces a solution which can be absorbed from the GI tract. Antiviral therapy further requires relatively large quantities of active ingredient to provide high serum concentrations of the active ingredient to avoid selection pressure for resistant strains. Requiring the tablet to contain high levels of I and limits excipients, carriers and diluents further which can be incorporated and increases the challenge to the formulator to design an acceptable and efficacious formulation.